9PPQ
Locally-refined Mu-Opioid Receptor bound with novel compound 0505 (3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol)
This is a non-PDB format compatible entry.
Summary for 9PPQ
| Entry DOI | 10.2210/pdb9ppq/pdb |
| EMDB information | 71775 |
| Descriptor | Mu-type opioid receptor, 3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol (2 entities in total) |
| Functional Keywords | gpcr, mu-opioid, partial agonist, active, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 38458.79 |
| Authors | |
| Primary citation | Wu, Y.,Vigneron, S.,Braz, J.,Srinivasan, K.,Fink, E.A.,Huang, X.P.,Xu, X.,Huebner, H.,Kim, J.Y.,Wang, J.,Pfeiffer, T.,Sakamoto, K.,Radchenko, D.S.,Rodriguiz, R.M.,Moroz, Y.S.,Irwin, J.J.,Gmeiner, P.,Billesboelle, C.,Roth, B.L.,Basbaum, A.I.,Manglik, A.,Wetsel, W.C.,Shoichet, B.K. Large Library Docking for Polypharmacology. J.Med.Chem., 2026 Cited by PubMed Abstract: Polypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the number of likely dual-activity molecules. In prospective docking of a 900-million molecule library against three target pairs (α/SERT, MOR/SERT, and α/MOR), we sought analgesic compounds. Both the α/SERT and SERT/MOR campaigns led to dual binders with low μM to high nM activities with high hit rates; tetrahydropyridines from the α/SERT campaign were also active against 5-HT. However, even though cryo-EM structures confirmed the docking-predicted poses, optimization struggled to improve potency. Still, in mouse behavioral assays, the most potent α/SERT compound (') was effective against pain without inducing conditioned place preference, and the molecule had potent antidepression and anxiolytic drug-like behavior, consistent with its SERT/5-HT activities. This study reveals both advantages and challenges of docking for polypharmacology. PubMed: 41712624DOI: 10.1021/acs.jmedchem.5c03810 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.34 Å) |
Structure validation
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